This invention generally relates to a site-specific antibiotic delivery system. More particularly, the present invention relates to a system that uses a carrier, such as a fibrin sealant, to deliver one or more antibiotics in situ. Specifically, the present invention relates to a system that can deliver a dose of antibiotics sufficiently high to overcome antibiotic-resistant bacteria.
Infection is the presence and successful multiplication of a microbe, such as a bacterium, virus, fungus or parasite, on or within a host or patient. An infection begins at a local nidus, or focal point, and typically results in local cellular injury due to toxins, competition for nutrients, intracellular replication, or a combination thereof. Once local cellular injury begins, the infected area is deemed an xe2x80x9cinfectious focus.xe2x80x9d Few antibiotics exhibit truly selective toxicity (i.e., only toxic to bacterial cells) and therefore result in side effects to the patient.
Side effects such as allergy, renal or hepatic injury, nerve cell damage, hypotension and neutropenia are common during the systemic use of antibiotics and thus limit the dose of antibiotics that can be used to treat the infection. These side effects are often due not only to a lack of selective toxicity, but also to the systemic absorption of the drug.
Since the 1940s, bacterial infections have been very successfully treated with antibiotics. In recent years, however, infection by multi-drug resistant (MDR) bacteria has been a growing problem. It is clear that the natural selection of antibiotic-resistant bacteria has resulted from excessive, prolonged and indiscriminate use of antibiotics, as well as over-the-counter availability, resulting in the increasing occurrence of infection by antibiotic-resistant bacteria. Increased antibiotic prophylaxis, the use of broad-spectrum agents and the poor education of patients and prescribers regarding the need and use of antibiotics have compounded the problem. For purposes of this specification, xe2x80x9cMDR,xe2x80x9d xe2x80x9cresistant,xe2x80x9d and xe2x80x9cantibiotic resistantxe2x80x9d bacteria refer to those bacteria so classified by federal testing agencies and as understood by one of ordinary skill in the art.
While there are numerous individual mechanisms, in general, antibiotics damage bacteria via discrete interaction with structural components or metabolic pathways. The biochemical mechanisms by which bacteria resist antibiotic activity may include prevention of drug entry into the cell, rapid extrusion of the drug from the cell, enzymatic inactivation of the drug or alteration of the molecular target. Also participating in the increasing resistance are the so-called xe2x80x9cnon-canonical mechanismsxe2x80x9d of gene dosage, heterologous induction, population resistance and low resistance synergism.
Current attempts to control infection by antibiotic-resistant bacteria include multiple-antibiotic therapies, supplementation of antibiotics with resistance inhibitors, immune modulating drugs, or combinations thereof. In many cases, systemic antibiotic concentrations exceed recommended levels, resulting in host toxicity.
Local therapy has some advantages over systemic therapy. First, as discussed, selective toxicity may not be achieved with conventional treatment. Second, systemic drug delivery may be unnecessary, unsafe or contra-indicated. Third, the maximum tolerable systemic dose of antimicrobial agent may not be efficacious due to poor vascularization, chronicity of infection or, more importantly, resistant microbes.
For purposes of this specification, xe2x80x9chost toxicity,xe2x80x9d xe2x80x9cwhole animal toxicity,xe2x80x9d or merely xe2x80x9ctoxicityxe2x80x9d refers to the subjective evaluation of the overall health of a patient as commonly known and understood by one of ordinary skill in the art. xe2x80x9cLow toxicityxe2x80x9d or xe2x80x9csubstantially non-toxicxe2x80x9d means there are no or only minor side effects, as determined, for example, by phase I studies. By contrast, xe2x80x9ccellular toxicityxe2x80x9d refers to injury to cells, such as measured by a fluorescein assay.
Fibrin sealant has several unique characteristics which make it suitable as a delivery matrix for pharmaceuticals, such as antibiotics, in a patient. First, fibrin sealant is hemostatic, i.e., reduces bleeding, which may facilitate healing. Second, the cross linked fibrin monomers of fibrin sealant create pores of proper size to trap and then release various pharmaceutical compounds. Third, release of trapped compounds is governed by a diffusion-dissolution mechanism, whereby the compound slowly dissolves when it is within the fibrin sealant matrix and also when it is released during the natural fibrinolysis process. For example, fibrin sealant has been used to deliver demineralized bone and bone morphogenetic proteins to repair bone defects in rats, to deliver acidic fibroblast growth factor-1 to Teflon shunts for endothelial cell recruitment forming artificial vascular grafts in dogs, to deliver antiproliferative chemotherapeutic agents in a mouse model of human ovarian cancer and to deliver antibiotics to treat infection. Commercial laboratories manufacture fibrin sealant components primarily for homoeostasis, such as the treatment of large surface area wounds in clotting-factor-deficient victims and the sealing of post-operative micro vascular leakage.
Antibiotic-supplemented fibrin sealant is also known. Greco et al., J. Biomed. Materials Res., 25:39 (1991), for example, discloses that antibiotics were found to be almost completely released by 96 hours, the greatest percentage of material (greater than 85 percent) having been released within 72 hours. Release of antibiotics over this relatively short time period most likely resulted from the rapid diffusion of small ionic molecules designed for maximum absorption during oral and parenteral delivery of a clinical formulation. This rapid release from fibrin sealant is clinically unacceptable when a longer course of treatment is required.
It is also known that a low dose of low-solubility antibiotics can be released from fibrin sealant to kill non-resistant bacteria. xe2x80x9cLow solubility,xe2x80x9d as used herein, refers to a species that one of ordinary skill in the art would describe as having a low solubility in water. Typically, such compounds are described in the Merck Index as xe2x80x9cpoorly soluble,xe2x80x9d xe2x80x9cpractically insoluble,xe2x80x9d xe2x80x9cslightly soluble,xe2x80x9d xe2x80x9csparingly soluble,xe2x80x9d etc. Generally, such compounds have a solubility less than about 2 mg/mL at room temperature. Preferably, such compounds have a solubility less than about 1 mg/mL.
A need remains for a formulation and method that will deliver a high dose of antibiotic that can overcome antibiotic-resistant bacteria with low host toxicity. Heretofore, the prior art cast serious doubt on the feasibility of such a formulation. First, Greco et al. and Thompson et al., Southern Medical J. 90:681 (1997), teach that increasing the loading dose of antibiotic onto fibrin sealant slows coagulation by interfering with the formation of fiber from fibrinogen. Second, heretofore it was uncertain whether the host toxicity could be kept low upon the administration of an effective high dose of antibiotic.
It is therefore an object of the present invention to provide a site-specific antibiotic delivery system.
It is another object to provide a fibrin-antibiotic delivery system such that the antibiotic releases from the fibrin in high concentrations in vivo.
It is yet another object of the present invention to provide a system that will deliver antibiotics in a dose sufficient to kill antibiotic-resistant bacteria.
It is another object of the present invention to provide a method for the site-specific delivery of antibiotics.
At least one or more of the foregoing objects, together with the advantages thereof over the known art relating to antibiotic delivery systems, which shall become apparent from the specification which follows, are accomplished by the invention as hereinafter described and claimed.
In general, the present invention provides a method of delivering a high dose of antibiotic comprising the step of inserting an antibiotic releasably bound to a carrier into an organism wherein the antibiotic is delivered in situ, wherein the dose of antibiotic delivered to the organism is sufficient to kill substantially all antibiotic-resistant bacteria present in an infectious focus.
The present invention also provides a site-specific antibiotic delivery system comprising a carrier and an antibiotic releasably bound to the carrier, wherein the antibiotic is delivered in situ and wherein the dose of antibiotic delivered to the organism is sufficient to kill substantially all antibiotic-resistant bacteria present in an infectious focus.